HRP940769A2 - (s)(+)-2-ethoxy-4-(n-(1-(2-piperidinophenyl)-3-methyl-1-butyl)-aminocarbonylmethyl)benzoic acid, medicines containing them, that compound and processes for the preparation thereof - Google Patents

Description

EP-B-0,147,850 describes, among others, racemic 2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl] aminocarbonylmethyl]-benzoic acid (code no. : AG-EE 388 ZW) formulas

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and in EP-B-0,207,331 two further polymorphic forms of this compound. This compound and its physiologically acceptable salts have valuable pharmacological properties, namely the effect on intermediate metabolism, especially the effect of lowering blood pressure.

Both enantiomers of this compound, namely (S)-(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]amino carbonyl methyl]-benzoic acid, (code no.: AG-EE 623 ZW) and (R)-(-)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl] aminocarbonylmethyl] -benzoic acid (code no.: AG-EE 624 ZW), we investigated the effect on lowering blood sugar in female rats.

Surprisingly, we found that the (S)-enantiomer (AG-EE 623 ZW) is an effective enantiomer and that its effect lasts more than 6 hours in rats.

Based on these results in the rat, the exclusive use of AG-EE 623 ZW is proposed for humans, which allows us to reduce the dose by 50% compared to the dose of AG-EE 388 ZW. We were able to confirm this, and relatively long-term action, in humans. In addition, we found in human studies that AG-EE 623 ZW again has surprising pharmacokinetic properties that could not be predicted based on the data for AG-EE 388 ZW. AG-EE 623 ZW therefore shows surprising therapeutic advantages compared to racemate AG-EE 388 ZW.

Surprising findings on humans are:

(a) AG-EE 623 ZW levels fall more rapidly towards zero than AG-EE 388 ZW levels, even at the same absolute dose, which was not expected based on the relatively long duration of action.

(b) Considering the achieved reduction in blood sugar, significantly lower plasma levels of AG-EE 623 ZW occur than would be expected when the dose of AG-EE 388 ZW is halved.

(c) The sugar-lowering effect occurs faster after the administration of AG-EE 623 ZW than after the administration of AG-EE 388 ZW.

The striking difference between both enantiomers is that the effective enantiomer, AG-EE 623 ZW, despite its relatively long-lasting effect, is surprisingly eliminated much faster than the ineffective enantiomer, AG-EE 624 ZW, as shown in Fig. 1 and 2. After administration the racemate's ineffective enantiomer, AG-EE 624 ZW, is therefore present not only as an unnecessary ballast in equally high plasma concentrations as the effective enantiomer, AG-EE 623 ZW, but in unexpectedly higher maximal and sustained levels. This is reflected, for example, in the application of tablets with 2 mg of AG-EE 388 ZW, i.e. tablets with 1 mg of AG-ee 623 ZW in 12 and 6 subjects, respectively, so that the maximum concentrations are 84 ± 25 and 28 ± 18 ng/ml, as well as concentrations after 4 hours 19 ± 8 or 0.7 ± 1.0 ng/ml, after 5 hours 13 ± 6 or 0.3 ± 0.7 ng/ml and after 6 hours 10 ± 6 or 0.3 ± 0, 7 ng/ml.

The surprisingly rapid onset of blood sugar lowering with AG-EE 623 ZW compared to AG-EE 388 ZW is particularly beneficial for diabetics, as the rapid onset results in optimal disease control.

Compared to the AG-EE 388 ZW application, there is therefore a surprising advantage of the AG-EE 623 ZW application in that it avoids that a large and long-term amount of substance unnecessarily burdens the organism, which is of great importance in long-term therapy, such as in the treatment of Diabetes Mellitus .

Human studies show that the new (S)-enantiomer, namely (S)-(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl ]aminocarbonylmethyl]-benzoic acid, as a carrier of blood sugar lowering efficiency due to its surprising and relatively long-term effect of unpredictable rapid elimination from the blood compared to AG-EE 388 ZW has better properties, which far exceed the "normal advantage" of one enantiomer in comparison with its racemate, namely the advantage of halving the dose.

The object of the proposed invention is therefore a new (S)-(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]amino carbonylmethyl]-benzoic acid, or ( S)-(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]amino carbonyl methyl]-benzoic acid, which is essentially optically pure, eg optical purity of at least ee = 95%, preferably 98 to 100%, its physiologically acceptable salts with inorganic or organic acids or bases, medicines containing that compound or its physiologically acceptable salts and procedures for its preparation.

In terms of the invention, the new compound is obtained according to the following procedures:

a) Chemical transformation of (S)-amine of the formula

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with a carboxylic acid of the general formula

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In which he represents

W carboxy group or a carboxy group protected with a protective residue, or with it, in the given example in the reaction mixture prepared by a reactive derivative is followed by cleavage of the protective residue as necessary.

As reactive derivatives of the compound of general formula II, for example, its esters, such as methyl-, ethyl- or benzyl ester, its thioesters, such as methylthio- or ethylthioester, its halides, such as acid chloride, its anhydrides or imidazolides, come into consideration.

The chemical conversion is expediently carried out in a solvent, such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, in the given example in the presence of an agent that activates the acid, or an agent for removing water, e.g. in the presence of ethyl chloride formate acid, chloroformic acid isobutyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide/ N,N'-dichlorohexylcarbodiimide, N,N'-dichlorohexylcarbodiimide/N-hydroxysuccinimide, N'N'-carbonyldiimidazole or N,N'-thiondiimidazole or triphenyl phosphine/carbon tetrachloride / or means that activate the amino group, for example phosphorus trichloride and in the given example in the presence of an inorganic base, such as sodium carbonate or a tertiary organic base, such as triethylamine or pyridine, which can simultaneously serve as solvents, at temperatures between -25 and 250°C , preferably at temperatures between -10°C and the boiling point of the solvent used. The chemical conversion can also be carried out without a solvent, and we can also separate the water produced during the conversion by azeotropic distillation, for example by heating it with toluene on a water separator, or by adding a drying agent, such as magnesium sulfate or molecular sieves.

If necessary, we then carry out the separation of the protective residue primarily hydrolytically, expediently either in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water , methanol, methanol/water, ethanol/water, water/isopropanol or water/dioxane, at temperatures between -10 and 120°C, for example at temperatures between room temperature and the boiling point of the reaction mixture.

The tert-butyl residue used as a protective residue can also be cleaved thermally, in the given example in an inert solvent, such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial acetic acid, and preferably in the presence of a strong acid, such as trifluoroacetic acid, hydrogen bromide, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid.

Furthermore, the benzyl residue used as a protective residue can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst, such as palladium/charcoal, in a suitable solvent, such as methanol, ethanol, ethanol/water, glacial acetic acid, acetic acid ethyl ester, dioxane or dimethylformamide.

b) Cleavage of the (S)-compound of the general formula

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in which it represents

And by hydrolysis, thermolysis or hydrogenolysis into a carboxy group a convertible group.

Examples of groups that can be hydrolyzed include functional derivatives of the carboxy group, such as its unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, amidines or anhydrides, nitrile group, tetrazolyl group, in the given example substituted 1,3-oxazole -2-yl or 1,3-oxazolin-2-yl group, i

as thermolytically cleavable groups, e.g. esters with tertiary alcohols, e.g. tert-butyl ester, and

as hydrogenolytically cleavable groups, e.g. aralkyl groups, e.g. benzyl group.

We meaningfully carry out the hydrolysis either in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water, water/methanol, water/ethanol , water/isopropanol or water/dioxane, at temperatures between -10 and 120°C, eg at temperatures between room temperature and the boiling point of the reaction mixture.

If A means in the compound of the general formula III, the nitrile or aminocarbonyl group of this group can be converted using 100% phosphoric acid into a carboxy group at temperatures between 100 and 180°C, preferably at temperatures between 120 and 160°C, or also with nitrite, e.g. with sodium nitrite, in the presence of an acid, such as sulfuric acid, and this is expediently used as a solvent at the same time, at temperatures between 0 and 50°C.

If A means in the compound of the general formula III, for example, a tert-butyloxycarbonyl group, the tert-butyl group can also be cleaved off thermally, in the given example in an inert solvent, such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane or glacial acetic acid, and preferably in the presence of a strong acid such as trifluoroacetic acid, hydrogen bromide, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, at temperatures between 0 and 100°C, preferably at temperatures between 20°C and the boiling point of the solvent used.

If A in the compound of the general formula III means, for example, a benzyloxycarbonyl group, the benzyl group can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst, such as palladium/charcoal, in a suitable solvent, such as methanol, ethanol, methanol/water, glacial acetic acid, acetic acid ethyl ester , dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, for example at room temperature, and a hydrogen pressure of 1 to 5 bar.

c) Conversion of the (S)-compound of the general formula

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in which means

W a carboxy group or an alkoxycarbonyl group together with 2 to 5 carbon atoms, whereby the alkyl part of the alkoxy group may be substituted with a phenyl group, with a compound of the general formula

[image]

in which it represents

With a nucleophilic exchangeable group, such as a halogen atom, a sulfonyloxy group or also together with an adjacent hydrogen atom a diazo group, followed by hydrolysis or hydrogenolysis as required.

The conversion is meaningfully carried out with the appropriate halide, sulfonic acid ester or sulfuric acid diester, for example with ethyl bromide, ethyl iodide, diethyl sulfate, ethyl ester of p-toluenesulfonic acid or ethyl ester of methanesulfonic acid, or with diazoethane, in the given example in the presence of a base, such as sodium hydride, potassium carbonate, sodium hydroxide, potassium tert-butylate or triethylamine, preferably in a suitable solvent, such as acetone, diethyl ether, tetrahydrofuran, dioxane, pyridine or dimethylformamide, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 50°C.

If W' in the compound of the general formula IV means a carboxy group, we can translate this into the corresponding ester compound.

If necessary, we carry out the following hydrolysis either in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, or in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water, methanol, methanol/water, ethanol, ethanol/water , water/isopropanol or water/dioxane, at temperatures between -10 and 120°C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture, or

subsequent hydrogenolysis in the presence of a hydrogenation catalyst, such as palladium/charcoal, in a suitable solvent, such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, at a hydrogen pressure of 1 to 10 bar.

d) Enantioselective reduction of a compound of the general formula

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in which it represents

W' a carboxy group or an alkoxycarbonyl group together with 2 to 5 carbon atoms, whereby the alkyl part of the alkoxy group can be substituted with a phenyl group,

Y group of the formula

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and hydrolysis follows if necessary.

The reduction is primarily carried out with hydrogen in the presence of a suitable chiral catalyst for hydrogenation in a suitable solvent, such as methanol, ethanol, isopropanol, ethyl acetate, dioxane, tetrahydrofuran, methanol/tetrahydrofuran, methanol/methylene chloride, ethanol/methylene chloride or isopropanol/methylene chloride, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 50°C, and hydrogen pressure between 1 and 1000 bar, preferably between 5 and 100 bar, and meaningfully with the addition of 0.1 to 5%, preferably 0.3 to 1%, of titanium (IV)-tetraisopropylate, and primarily with the exclusion of oxygen, which is in the air. First of all, we perform the reduction with the (Z)-form of the compound of the general formula VI.

Suitable metal complexes with ligands, such as Ru (OCO-CH3) 2[ (S)-BINAP], Ru2Cl4[(S)-BINAP]2 x N(C2H5)3, Rh[ (S) -BINAP-NBD]ClO4 or Rh[(-)-NORPHOS-COD]BF4.

During catalytic hydrogenation, the benzyloxycarbonyl group can be co-reduced at the same time and converted into a carboxy group.

If necessary, we then carry out hydrolysis either in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water, methanol, methanol/water , ethanol, ethanol/water, water/isopropanol or water/dioxane, at temperatures between -10 and 120°C, eg at temps. between room temperature and the boiling point of the reaction mixture.

e) Oxidation of the (S)-compound of the general formula

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in which it represents

W" to the carboxy group by oxidizing the translatable group.

As a group that can be oxidized, for example a formyl group and its acetals, a hydroxymethyl group and its ethers, an unsubstituted or substituted acyl group, such as an acetyl, chloroacetyl, propionyl, malonic acid-(1)-yl group or a malonester-( 1)-yl group.

The conversion is carried out with an oxidizing agent in a suitable solvent, such as water, glacial acetic acid, methylene chloride, dioxane, glycoldimethylether, at temperatures between 0 and 100°C, meaningfully at temperatures between 20 and 50°C. The conversion is primarily carried out with silver oxide/sodium alkali, manganese dioxide/acetone or methylene chloride, hydrogen peroxide/sodium alkali, bromine or chlorine/sodium or potassium alkali, chromium trioxide/pyridine or pyridinium chlorochromate.

f) Separation of the mixture, which consists of an arbitrary amount of (S)-enantiomers of the general formula

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and arbitrary amounts of the (R)-enantiomer of the general formula

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in which it means

W' is a carboxy group or an alkoxycarbonyl group together with 2 to 5 carbon atoms, whereby the alkyl part of the alkoxy group can be substituted with a phenyl group, preferably a 50/50 mixture, via its diastereomeric adducts, complexes or salts, followed by hydrolysis or hydrogenolysis if necessary .

The separation is primarily performed using column or HPL chromatography with the formation of diastereomeric adducts or complexes on the chiral phase.

If necessary, we then carry out hydrolysis either in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trichloroacetic acid, or in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water, methanol, methanol/water , ethanol, ethanol/water, water/isopropanol or water/dioxane, at temperatures between -10 and 120°C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture, or

then hydrogenolysis in the presence of a hydrogenation catalyst, such as palladium/charcoal, in a suitable solvent, such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, at a hydrogen pressure of 1 to 10 bar.

Thus, according to the invention, the obtained (S)-enantiomer with an optical purity of at least 90% can be converted by fractional crystallization into an (S)-enantiomer with an optical purity of at least 95%, preferably 98 to 100%.

The same applies to the (S)-compounds with the formulas III/IV and VII within the meaning of the invention, especially for their esters.

Thus, according to the invention, the obtained (S)-enantiomer can be converted into its salts, especially for pharmaceutical use into its physiologically acceptable salts with inorganic or organic acids or also bases. As acids, for example, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid, and as bases sodium hydroxide, potassium hydroxide, calcium hydroxide come into consideration. , cyclohexylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine or lysine.

Compounds with formulas 1 to IX, used as starting substances, are partially known from the literature, that is, they are obtained according to known procedures.

The (S)-amine of formula I can be obtained from the corresponding racemic amine

with resolution of the racemate, e.g. fractional crystallization of diastereomeric salts with suitable optically active acids, preferably with N-acyl-L-glutamic acid, and if necessary recrystallization, as well as subsequent decomposition of the salt,

with column or HPL-chromatography on chiral phases, in the given example in the form of an acyl derivative,

or with the formation of diastereomeric compounds, their separation and then cleavage.

Furthermore, (S)-amine can be obtained with high enantioiaer purity

with enantioselective reduction by means of hydrogen in the presence of a suitable chiral catalyst for hydrogenation from the corresponding N-acyl-ketimine or enamide, meaningfully with the addition of 0.1 to 5% titanium tetraisopropylate, and in the given example then splitting off the acyl residue, as a formyl or acetyl residue,

with the diastereoselective reduction of the corresponding, chirally substituted ketimine or hydrazine on the nitrogen atom by hydrogen in the presence of a suitable hydrogenation catalyst, expediently with the addition of 0.1 to 5% titanium tetraisopropylate, and in the given example followed by cleavage of the chiral auxiliary residue, e.g. (S)-1 -phenethyl residue, with catalytic hydrogenolysis, or

with the diastereoselective addition of a suitable organometallic compound, preferably a Grignard or lithium compound, to a suitable aldimine chirally substituted on the nitrogen atom, in the given example with the addition of 0.1 to 10% titanium tetraisopropylate, followed by hydrolysis and in the given example followed by the separation of the obtained diastereomers and then the separation of the chiral of an auxiliary residue, e.g. (R)-1-phenethyl residue, with catalytic hydrogenolysis,

and if necessary with the formation of salts with suitable optically active acids, preferably with N-acetyl-L-glutamic acid and if necessary one or more times by recrystallization, as well as then decomposition of the salt.

Compounds with general formulas III, IV and VII, used as starting substances, are obtained by converting (S)-amine 1 with the appropriate carboxylic acid or its reactive derivatives, and in the given example, the used protective residue is removed.

The compound of the general formula VI, used as a starting substance, is obtained by acylation of the corresponding imino compound or its organometallic complexes with a corresponding carboxylic acid or its reactive derivatives, followed by possible cleavage of the ester group.

The new (S)-enantiomer is practically non-toxic; e.g. after one application of 1000 mg/kg p.o. (suspension in 1% methylcellulose) each time five male and five female rats and not one animal died in the subsequent observation time of 14 days.

On the basis of their pharmacological and pharmacokinetic properties, the (S)-enantiomer AG-EE 623 ZW and its physiologically acceptable salts suitable for the treatment of Diabetes mellitus are prepared according to the invention. For this, AG-EE 623 ZW or its physiologically acceptable salts, in the given example in combination with other effective substances, can be incorporated into the usual galenic forms of preparations, such as tablets, dragees, capsules, powders, suppositories, suspensions or injection solutions. The individual dose for an adult is 0.1 to 20 mg, preferably 0.25 to 5 mg, especially 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 or 5.0 mg one, two or three times a day.

A further object of the proposed invention is the new (S)-amine of formula I, which represents a valuable intermediate for the preparation of the new (S)-enantiomer, as well as its addition salts with inorganic or organic acids.

A further subject of the proposed invention are new compounds with general formulas III, IV and VII, which represent valuable intermediates for the preparation of the new (S)-enantiomer, as well as its addition salts with inorganic or organic acids.

The following examples explain the invention in more detail.

EXAMPLE A

(S)-1-(2-piperidino-phenyl)-3-methyl-1-butylamine

To a solution of 122 g (0.495 mol) of racemic 1-(2-piperidino-phenyl)-3-methyl-1-butylamine in 1000 ml of acetone, we add 93.7 g (0.495 mol) of N-acetyl-L-glutamic acid while stirring. Heat on a steam bath under reflux and add methanol in portions (about 80 ml in total) until a clear solution is obtained. After cooling and standing overnight at room temperature, the resulting crystals are sucked off, washed twice with 200 ml of cold acetone (-15°C) and dried. The product obtained [98.9 g; tal. :163-166°C; [α]D20= +0.286° (c = 1 in methanol)] is recrystallized from 1000 ml of acetone with the addition of 200 ml of methanol, thereby obtaining (S)-1-(2-piperidino-phenyl)-3-methyl-1- butylitlin as an addition salt of N-acetyl-L-glutamic acid.

Yield: 65.1 g (60.4 % of theory)

melting point: 168-171°C

[image]

[α]D20= 0.357° (c = 1 in methanol)

The free amine is obtained as an oil with release, for example, with sodium hydroxide or ammonia solution, extraction, for example, with toluene, ether, ethyl acetate or methylene chloride, as well as with drying, filtering and evaporation of the extract in a vacuum.

We prove the (S)-configuration of the amine as follows:

Conversion of the amine with (S')-1-phenethylisocyanate in ether to the corresponding urea derivative [mp: 183 to 184°C; [α]D20= -2.25° (c = 1 in methanol)], crystal growth from ethanol/water (8/1) and then X-ray structural analysis, which gives the (S,S')-configuration for the urea derivative and s thus (S)-configuration for the amine used.

We determine the enantiomeric purity as follows:

1. Acetylation of the amine sample with 1.3 equivalents of acetic anhydride in glacial acetic acid overnight at 20°C.

2. Examination of the N-acetyl derivative (m.p. 128 to 132°C) by HPLC on a chiral phase HPLC column with chiral gases from the company Baker, in which (S)-N-(3,5-dinitrobenzoyl)-2 -phenyl-glycine covalently bound to aminopropyl-silica gel (grain size: 5 µm, spherical, pore width 6 nm, column length: 250 mm with an internal diameter of 4.6 mm; eluent; n-hexane/isopropanol (100/5) elution rate: 2 ml/min;

temperature: 20°C; UV-detection at 254 nm).

Establishment: Peak 1(R); Peak 2(S) = 0.75%: 99.25%,

ee (enantiomeric excess) = 98.5 % (S).

Using an ethereal solution of hydrogen chloride, we can convert (S)-amine into its dihydrochloride hydrate.

[image] [α]D20= +26.1° (c = 1 in methanol)

EXAMPLE B

N-acetyl-N-[1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl]-amine

4.7 ml (81.8 mmol) of glacial acetic acid, 25.7 g ( 98.2 mmol) of triphenylphosphine, 34.2 ml (245 mmol) of triethylamine and 7.9 ml (81.8 mmol) of carbon tetrachloride, and stirred for 18 hours at room temperature. Then evaporate in a vacuum and distribute between ethyl acetate and water. The organic extract is dried and filtered, and evaporated in a vacuum. The evaporated residue is purified by column chromatography on silica gel (toluene/ethylacetate = 10/1), whereby first the (E)-form and then the (Z)-form are eluted.

(E)-form:

Yield: 6.1 g (26 % of theory)

m.p.: 135-137°C (ethyl acetate/petroleum ether)

[image]

(Z)-form:

Yield: 3.1 g (13 % of theory)

melting point: 140-143°C (ethyl acetate)

[image]

EXAMPLE C

N-acetyl-N-[1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl]-amine

In a solution of 44 g (0.18 mol) of freshly prepared isobutyl-(2-piperidino-phenyl)-ketimine in 440 ml of toluene, 17 ml (0.18 mol) of acetic anhydride are added dropwise with stirring at an internal temperature of 0°C. Stir for another 3 hours at 0°C and 15 hours at room temperature, then evaporate in a vacuum, dissolve the evaporated residue in ethyl acetate and shake it several times with an aqueous solution of sodium bicarbonate. The organic phase is dried, filtered and evaporated in a vacuum. The evaporated residue is purified by column chromatography on silica gel (toluene/ethyl acetate 5/1), whereby first the (E)-form and then the (Z)-form are eluted.

(E)-form:

Yield: 3.0 g (5.8% theoretical)

(Z)-form:

Yield: 17.8 g (34.5 % of theory)

m.p.: 139-141°C (ethyl acetate)

[image]

EXAMPLE D

N-acetyl-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine

0.57 g (1.99 mmol) of (Z)-N-acetyl-N-[1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl]amine with m.p. 139 to 141°C, dissolve in 10 ml of gasified solvent mixture (methanol/methylene chloride = 5/1) in an argon atmosphere and add 16.8 mg (1 mol %) of NOYORI catalyst Ru(O-acetyl)2[(S) -BINAP] (prepared from [Ru(COD)Cl2]n with (S)-BINAP[=(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl], triethylamine and sodium acetate) and 3.4 mg (0.5 mol %) of titanium tetraisopropylate in 10 ml of a gaseous solvent mixture (methanol/methylene chloride = 5/1). Place the reaction mixture in an autoclave, evacuated at 10-2 mbar. Wash several times with hydrogen at 4 bar and then hydrate at 30°C and 100 bar until hydrogen bonding is complete (170 hours). Then evaporate the brown-red solution in a vacuum, boil the evaporated residue with 30 ml of n-hexane under reflux and filter off the undissolved hot solution. Crystallization occurs when the filtrate is cooled.

Yield: 0.31 g (54 % of theory)

Melting point: 127-131°C

Enantiomeric purity: ee = 82% (S) [HPLC method: see example A].

14% of racemic N-acetyl-amine with m.p. 154-156°C.

EXAMPLE E

(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl-amine

We heat 1 g (3.47 mmol) of N-acetyl-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine (m.p.: 128-133°C; ee = 99.4 %) in 10 ml of concentrated hydrochloric acid for 5.5 hours under reflux, cool and pour into a mixture of concentrated ammonia and ice. Extract twice with ethyl acetate, wash the organic phase with water, dry and filter, and evaporate in a vacuum.

Yield: 0.84 g (98.8 % of theory) of oily amine.

Back-acetylation with 0.42 ml (1.3 equiv) of acetic anhydride in 8.4 ml of glacial acetic acid overnight at room temperature, evaporation in vacuo, partitioning the evaporated residue between ethyl acetate and saturated aqueous sodium carbonate, as well as drying, filtering and evaporation of the organic extract in a vacuum gives 0.83 g (84.7 % of theory) of N-acetyl-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine ( mp: 130-132°C; ee = 99.4%).

EXAMPLE F

2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl)-aminocarbonylmethyl-benzoic acid ethyl ester

Prepared from isobutyl-(2-piperidino-phenyl)-ketimine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogously to example B. Chromatographic purification in a column on silica gel (toluene/acetone = 10/1), whereby we first elute (E )-form and then (Z)-form.

(E)-form:

Utilization: 4 % theor.,

melting point: 101-103°C

[image]

(Z)-form:

Utilization: 28.1 % of theory,

m.p.: 124-127°C (petroleum ether/toluene = 5/1)

[image]

EXAMPLE Mr

N-[(S')-1-phenethyl]-N-[(S)-1-(20piperidino-phenyl)-3-methyl-1-butyl]-amine

17 g (49 mmol) of N-[(S')-1-phenethyl]-isobutyl-(2-piperidino-phenyl)-ketimine with a boiling point of 150-155°C/0.4 mbar [prepared from isobutyl-(2- of piperidino-phenyl)-ketone and (S')-1-phenethyl-amine (Fluka company, ee = 99.6%) in toluene + triethylamine with dropwise addition of a solution of titanium tetrachloride in toluene] dissolve in 170 ml of anhydrous ethanol. We add 1.7 g of titanium tetraisopropylate and 8 g of Raney's nickel and hydrate at 50°C and 200 bar of hydrogen. After 20 hours, we add a further 8 g of Raney's nickel and hydrate under the same conditions for another 52 hours. The catalyst is filtered over a layer of celite on a G3 plate and the filtrate is evaporated in a vacuum.

Yield: 13.1 g (76.6 % of theory)

Melting point: 152°C/0.27 mbar

[image] [α]D20= -55.3° (c = 1.1 in methanol)

Diastereomeric purity was determined using HPLC on a Lichrosorb RP18-HPLC column from E. Merck (Germany); column length: 250 mm with an inner diameter of 4 mm, particle size: 7 µm; eluent: methanol/dioxane/0.1% aqueous sodium acetate, adjusted with acetic acid to pH = 4.05 (135/60/5); temperature: 23°C; UV detection at 254 nm.

Est.: Peak 1(S,S'): Peak 2(R,S') = 98.4 %: 1.4 %,

de (diastereomeric excess) = 97.0 % (S.S').

EXAMPLE H

(S)-1-(2-piperidinophenyl)-3-methyl-1-butylamine

12.5 g (36 mmol) of N-[(S')-1-phenethyl]-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine with de = 97.0% (S.S') dissolve in 125 ml of water and 3.6 ml of concentrated hydrochloric acid. We add 1.3 g of palladium/charcoal (10%) and hydrate at 50°C and 5 bar of hydrogen. After the completion of hydrogen bonding (10 hours), the catalyst is filtered through a celite layer. The filtrate is made alkaline with concentrated ammonia with the addition of ice and extracted with ethyl acetate. The organic extract is dried and extracted with ethyl acetate. The organic extract is dried and filtered, and evaporated in a vacuum.

Yield: 6.4 g (72.1 % of theory)

Melting point: 115-117°C/0.53 mbar

enantiomeric purity: ee = 93.5 % (S) [HPLC-method (after previous acetylation): see example A].

EXAMPLES

N-[(R')-1-phenethyl]-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine

In a bath at 60°C, a solution of 27.4 mmol (4 equivalents) of isobutylmagnesium bromide in 22 ml of anhydrous tetrahydrofuran is added dropwise with stirring to a solution of 2 g (6.84 mmol) of N-[(R')-1-phenethyl]-(2- piperidino-benzaldimine) [prepared from equimolar amounts of 2-piperidino-benzaldehyde and (R')-1-phenethylamine by standing overnight at room temperature and then drying with sodium sulfate in an ethereal solution] in 20 ml of anhydrous tetrahydrofuran. After 18 hours, we raise the temperature of the bath to 80°C, and add another two equivalents of isobutylmagnesium bromide in 11 ml of tetrahydrofuran. After each 12-hour mixing at 80°C, 2 equivalents of isobutylmagnesium bromide solution are added once more. After about 90 hours at 80°C, cool, add an excess of concentrated hydrochloric acid and evaporate to dryness in a water jet vacuum. The evaporated residue is dissolved in water and made alkaline with concentrated ammonia. Extract with ether, dry the organic extract over sodium sulfate, filter and evaporate in a vacuum. The evaporated residue is purified by column chromatography on silica gel (toluene/acetone = 95/5).

Yield: 0.20 g (8.3 % theory),

Melting point: <20°C

Diastereomeric purity is determined as in example G using HPLC.

Est.: Peak 1(R,R'): Peak 2(S,R') = 4.4 %: 95.6 %,

de (diastereomeric excess) = 91.2 % (S, R').

In the analogous continuation with 2.0 g of Schiff's base and together with 6 equivalents of isobutylmagnesium bromide in toluene/tetrahydrofuran (4/1) as well as with the addition of 5% titanium(IV)-tetraisopropylate and 60 hours of heating at 100°C in a glass flask, we achieve utilization of 5 % with de = 97.6 % (S,R').

EXAMPLE K

(S)-1-(2-piperidino-phenyl)-3-methyl-1-butylamine

We hydrate a solution of 0.15 g (0.428 mmol) of N-[(R')-1-phenethyl]-N-[(S)-1-(2-piperidino-phenyl)-3-methyl-1-butyl]-amine (de = 91.2 %), 0.47 ml (0.47 mmol) of 1N hydrochloric acid and 1.5 ml of water in the presence of 20 mg of palladium/charcoal (10 %) for 5 hours at 50°C and 3, 4 bars of hydrogen. Filter through silica gel, make alkaline with concentrated ammonia and extract with ethyl acetate. The extract is dried, filtered and evaporated in a vacuum.

Yield: 0.066 g (62.8 % of theory),

Melting point: <20°C

Enantiomeric purity: ee = 87.6 % (S) [HPLC-method (after previous acetylation): see example A].

EXAMPLE 1

(S)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

To a solution of 0.47 g (1.91 mmol) of (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5 %) in 5 ml of anhydrous acetonitrile, add 0, 48 g (1.91 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 0.60 g (2.29 mmol) of triphenylphosphine, 0.80 ml (5.73 mmol) of triethylamine and 0.18 ml (1, 91 mmol) of carbon tetrachloride, and stir for 20 hours at room temperature. Then evaporate in a vacuum and distribute between ethyl acetate and water. The organic extract is dried and filtered, and evaporated in a vacuum. The evaporated residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 10/1).

Yield: 0.71g (77.3% theory),

Tal. = 110-112°C

[image]

Enantiomeric purity is determined by HPLC on an HPLC column with chiral phases from the company Baker, where (S)-N 3,5-dinitrobenzoyl-leucine is covalently bound to aminopropyl-silica gel. Grain size: 5 µm, spherical, pore width: 60 nm;

column length: 250 mm with an internal diameter of 4.6 mm; eluent: n-hexane/tetrahydrofuran/methylene chloride/ethanol (90/10/1/1); elution rate: 2 ml/min; temperature: 20°C;

UV detection at 242 nm.

Est.: Peak 1(R): Peak 2(S) = 0.75 %: 99.25 %,

ee = 98.5% (S) .

EXAMPLE 2

(S)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

In a solution of 2.71 g (11 mmol) of anhydrous (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 30 ml of absolute toluene, at room temperature 2 .77 g (11 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and mix until a solution is formed. Then add 2.38 g (11.55 mmol) of N,N'-dicyclohexylcarbodiimide and mix at room temperature. After 24 hours, add another 0.54 g (2.14 mmol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and 0.48 g (2.33 mmol) of N,N'-dicyclohexyl-carbodiimide, and stir overnight. Then cool down to an internal temperature of +5°C and filter off the precipitate through a sieve, which is washed once with 5 ml of toluene. The combined toluene filtrates are evaporated in a vacuum to a volume of about 10 ml. We heat the solution obtained in this way on a steam bath and add petroleum ether in portions (55 ml in total) until permanent cloudiness. Cool in ice, during which crystallization occurs. We filter it through a sieve and dry it at 75°C/5.3 mbar. The obtained product (4.57 g; m.p. 111-112°C; ee=98.9%) is suspended in 50 ml of petroleum ether. Heat on a steam bath and add as much toluene in portions (8 ml in total) until a solution is formed. Then we cool it in ice and filter the crystals through a sieve, and dry them at 75°C/5.3 mbar.

Yield: 3.93 g (74.3 % of theory),

melting point: 117-118°C

[image] [α]D20= +9/4º (c = 1.01 in methanol)

Enantioiner purity: ee = 99.9 % [HPLC method: see example 1].

EXAMPLE 3

(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid

A solution of 3.79 g (7.88 mmol) of (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester (ee=99.9%) in 37 ml of ethanol, mix in a bath at 60°C and add 10 ml (10 mmol) of 1N sodium hydroxide solution. After 4 hours of stirring at 60°C, add 10 ml (10 mmol) of 1N hydrochloric acid to the warm mixture and let it cool to room temperature. After separating and standing overnight, cool with stirring in ice for another hour. The crystals are filtered through a sieve and washed twice with 5 ml of water each. Then we dry at 75°C and finally in a vacuum dryer over phosphorus pentoxide at 100°C/5.3 mbar.

Yield: 3.13 g (87.7 % of theory),

m.p.: 130-131°C (high melting point form)

[image] [α]D20= +7.45° (c = 1.06 in methanol)

Enantiomeric purity was determined using HPLC on an HPLC column with chiral phases from ChromTech (Sweden) with an AGP (α-1-acid glycoprotein) phase; inner diameter: 4.0 mm; length: 100 mm; particle diameter: 5 µm. Temperature: 20°C; eluent: aqueous solution of KH2PO4 (=A) + 20% acetonitrile (=B), gradient increase in 4 minutes to 40% (B); elution rate: 1 ml/min; UV detection at 240 nm. Retention time (S)-enantiomer: 2.7 mm; retention time (R)-enantiomer: 4.1 mm.

Est.: (S):(R) = 99.85 %: 0.15 %,

ee = 99.7% (S) .

During recrystallization of the sample from ethanol/water (2/1), the melting point does not change.

When heating the sample in petroleum ether/toluene (5/3), filtering the insoluble part (melting point: 130-131°C) and rapid cooling, we obtain the form of the title compound with a low melting point of 99-101°C.

[image]

The low-melting-point forms and the high-melting-point forms differ in their infrared KBr-spectra, while they do not differ in their infrared solution spectra.

If we heat a sample of a form with a low melting point above its melting point, we notice a second melting point at 127-130°C.

If we recrystallize a sample of the form with a low melting point with ethanol/water (2/1), we obtain a form with a high melting point.

The high-melting-point form and the low-melting-point form are examined using "Differential Scanning Calorimetry (DSC)" (apparatus Mettler, TA-300-system; measuring station: DSC 20; company Mettler, CH-8306 Greifensee, Switzerland) with the following result:

[image]

EXAMPLE 4

(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

0.79 g (1.65 mmol) ethyl ester (Z)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl)-aminocarbonylmethyl] -benzoic acid with a melting point of 124-127°C is dissolved in 10 ml of a gaseous solvent mixture (methanol/methylene chloride = 5/1) in an argon atmosphere and 17 mg of NOYORI-catalyst Ru (O-acetyl)2[(S)- BINAP] (prepared from [Ru(COD)Cl2]n with (S)-BINAP [=(S)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl], triethylamine and sodium acetate) and 3 mg of titanium tetraisopopylate in 10 ml of gasified solvent mixture (methanol/methylene chloride = 5/1). Place the reaction mixture in an autoclave, evacuated at 10-2 mbar. Wash 5 times with hydrogen at 5 bar and then hydrate at 30°C and 100 bar until the end of hydrogen binding (154 hours). The brown-red solution is evaporated in a vacuum, the evaporated residue is dissolved in 80 ml of ether, the insoluble brown flakes are filtered using activated carbon and the clear light yellow filtrate thus obtained is evaporated in a vacuum. Boil the evaporated residue (0.60 g) with 60 ml of n-hexane under reflux and filter the undissolved hot. Let the filtrate stand overnight at room temperature. In doing so, we filter the secreted crystals.

Yield: 0.45 g (56.7 % of theory),

m.p.: 131-133°C (after sintering above 120°C)

Enantiomeric purity: ee = 39% (S) [HPLC method: see example 1].

EXAMPLE 5

(S)-2-Ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

In a solution of 0.68 g (1.15 mmol) of ethyl ester (S)-2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid acids [m.p. : 125-126°C; [α]D20= +12.87° (c = 1.01 in methanol)] add 0.05 g (1.15 mmol) of sodium hydride/55% in oil to 5 ml of anhydrous dimethylformamide and mix 0.5 hours at room temperature. Then a solution of 0.12 ml (1.15 mmol) of ethyl iodide in 2.5 ml of anhydrous dimethylformamide is added dropwise and stirred for 5 hours at room temperature. Evaporate in a vacuum, distribute between dilute sodium hydroxide solution and chloroform, dry the organic extract, filter and evaporate in a vacuum. The evaporated residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 10/1).

Yield: 0.48 g (67 % of theory),

melting point: 110-112°C

[image] Enantiomeric purity: ee = 98.5 % (S) [HPLC method: see example 1].

EXAMPLE 6

(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

Prepared from (S)-2-hydroxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid, analogously to example 5, with 2 equivalents of sodium hydride and 2 equivalents of ethyl iodide.

Utilization: 42% theoretical,

melting point: 110-112°C

[image] Enantiomeric purity: ee = 98.3 % (S) [HPLC method: see example 1].

EXAMPLE 7

Ethyl ester (S) (+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylethyl-benzoic acid and ethyl ester (R) (-)- 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid

920 mg of (±)-2-ethoxy-4-[N- (1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester is separated in individual doses of 10 mg per preparative HPLC column with chiral phases from Baker, where (S)-N-3,5-dinitrobenzoyl-leucine is covalently bound to aminopropyl silica gel. (Grain size 40 um; column length: 250 mm internal displacement 20 mm; eluent: n-hexane/tetrahydrofuran/ethanol/methylene chloride (180/20/3/2) ; elution rate: 21.25 ml/min; temperature: 27°C; UV-detection at 285 nm), whereby we first elute the (R) (-)-enantiomer (Peak 1) and then the (S)(+)-enantiomer (Peak 2).

From the appropriately separated and collected fractions, after evaporation in a vacuum, we get:

Fraction "Peak 1" (R): 423 mg (raw),

Fraction "Peak 2" (S): 325 mg (raw).

To separate impurities (among others, the stabilizer 2,6-di-tert-butyl-4-methylphenol, which contains tetrahydrofuran), both fractions are purified each time by column chromatography on silica gel (toluene/acetone = 10/1).

(R)(-)-enantiomer:

Yield: 234.5 mg (51 % of theory),

m.p.: 122-124°C (petroleum ether + acetone)

[image] [α]D20= -8.3° (c = 1 in methanol) (S)-enantiomer:

Yield: 131.2 mg (28.5% theory),

melting point: 122-124°C (petroleum ether/acetone = 8/1)

[image] [α]D20= +8.3° (c = 1 in methanol)

A Chiralcel OD column from Daicel is also suitable for enantiomer separation. On a column with a length of 250 mm and an internal diameter of 4.6 mm (eluent: absolute ethanol/n-hexane + 0.2% diethylamine) = 5/95; temperature: 40°C; UV detection at 245 nm) we elute the (R)-enantiomer after 6.8 minutes and the (S)-enantiomer after 8.5 minutes.

EXAMPLE 8

(R) (-)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid x 0.4 H2O

Prepared from 150 mg (0.312 mmol) ethyl ester (R)(-)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonyl-methyl]- benzoic acid [melt.: 122-124°C;

[α]D20= -8.3° (c = 1 in methanol)] by saponification with 1N sodium hydroxide solution in ethanol analogously to example 3.

Yield: 95.8 mg (66.7 % of theory),

m.p.: 103 - 105°C (toluene/petroleum ether)

[image] Molar peak M+: calc.: 452

mouth: 452

[α]D20 =6.50 (c = 1 in methanol)

Enantiomeric purity: ee = 99.7 % (R) [HPLC method: see example 3].

EXAMPLE 9

(S)(+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid x 0.4 H2O

Prepared from 89 mg (0.198 mmol) ethyl ester (S)(+)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid [tal. : 122-124°C; [α]D20 = +8.3° (c = 1 in methanol)] by saponification with 1N sodium hydroxide solution in ethanol analogously to example 3.

Yield: 44.5 mg (48.8% theoretical),

m.p.: 102-103°C (toluene/petroleum ether)

[image] [α]D20= +6.7° (c = 1 in methanol)

Enantiomeric purity: ee = 99.6 % (S) [HPLC method: see example 3].

EXAMPLE 10

(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid

We hydrate 0.26 g (0.47 mmol) of benzyl ester (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid (mp: 91-92°C; [α]D20= +9.5°; c = 1.05 in methanol) in 10 ml ethanol on 0.12 g palladium/charcoal (10%-tn) at 50° C and 5 bars of hydrogen. After 5 hours, the catalyst is filtered through Kieselgur and evaporated in a vacuum. The evaporated residue is crystallized from ethanol/water (2/1).

Yield: 0.15 g (70% theoretical),

melting point: 130-131°C

[image] Enantiomeric purity: ee = 99.6 % (S) [HPLC method: see example 3].

EXAMPLE 11

(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl-benzoic acid

102 mg (0.20 mmol) tert-butyl ester (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid ( m.p.: 122-123°C; [α]D20= +8.7°; c = 1 in methanol) in 5 ml of benzene is heated for half a day under reflux together with several crystals of p-toluenesulfonic acid hydrate. Then, after thin-layer chromatography according to the RF value and the mass spectrum, the desired product is created. Melting point: 129-131°C

Molar peak M+: calcd. : 452

mouth: 452

EXAMPLE 12

(S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid

200 mg (0.395 mmol) of tert-butyl ester (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoic acid (m.p. 122-123°C; [α]D20= +8.7°; (c = 1, in methanol)] in 2 ml of ethylene chloride is stirred overnight at room temperature together with 0.45 g (3.95 mmol) of trifluoroacetic acid Evaporate in a vacuum and distribute the evaporated residue between an aqueous solution of sodium hydrogencarbonate and ethyl acetate. Dry the organic extract, filter and evaporate in a vacuum. Crystallize the evaporated residue from ethanol/water (2/1).

Yield: 115 mg (64.7% theoretical),

melting point: 126-128°C

[image] [α]D20 = +6.97° (c = 0.975 in methanol)

Enantiomeric purity: ee = 99.6% [HPLC method: see example 3].

EXAMPLE 13

Tablet with 0.25 mg AG-EE 623 ZW

One tablet contains:

0.250 mg of active substance

0.125 mg of N-methylglucamine

0.038 mg polyvinylpyrrolidone

0.075 mg of polyoxyethylene polyoxypropylene polymer

0.150 mg of microcrystalline cellulose

Preparation:

Dissolve the effective substances and auxiliary substances in water at 90°C, that is, suspend the microcrystalline cellulose and evaporate the dispersion in a vacuum. Sift the dry mass to a loop width of 1 mm. The following ingredients are mixed with the granule of the active substance for the tablet:

24.862 mg sodium carboxymethyl starch

24,000 mg of microcrystalline cellulose

0.500 mg magnesium stearate

50,000 mg

Round plan-parallel tablets of 50 mg and 5 mm in diameter are pressed from this mixture.

EXAMPLE 14

Tablets with 0.5 mg AG-EE 623 ZW

One tablet contains:

0.500 mg of effective substance

0.250 mg of N-methylglucamine

0.075 mg polyvinylpyrrolidone

0.150 mg of polyoxyethylene polyoxypropylene polymer

0.300 mg of microcrystalline cellulose

Preparation:

Dissolve the effective substances and auxiliary substances in water at 90°C, that is, suspend the microcrystalline cellulose and evaporate the dispersion in a vacuum. Sift the dry mass to a loop width of 1 mm.

The following ingredients are mixed with the granule of the active substance for the tablet:

24.225 mg sodium carboxymethyl starch

24,000 mg of microcrystalline cellulose

0.500 mg magnesium stearate

50,000 mg

Round plan-parallel tablets of 50 mg and 5 mm in diameter are pressed from this mixture.

EXAMPLE 15

Tablet with 1.0 mg AG-EE 623 ZW

One tablet contains:

1.00 mg of active substance

0.05 mg of N-methylglucamine

0.15 mg polyvinylpyrrolidone

0.03 mg of polyoxyethylene polyoxypropylene polymer

0.60 mg of microcrystalline cellulose

Preparation:

Dissolve the effective substances and auxiliary substances in water at 90°C, that is, suspend the microcrystalline cellulose and evaporate the dispersion in a vacuum. Sow the dry mass to a loop width of 1 mm.

The following ingredients are mixed with the granule of the active substance for the tablet:

23.22 mg sodium carboxymethyl starch

24.00 mg microcrystalline cellulose

0.50 mg magnesium stearate

50,000 mg

Round plan-parallel tablets of 50 mg with a diameter of 5 mm are formed from this mixture.

EXAMPLE 16

Tablet with 1.5 mg AG-EE 623 ZW

One tablet contains:

1,500 mg of effective substance

0.750 mg of N-methylglucamine

0.225 mg polyvinylpyrrolidone

0.045 mg of polyoxyethylene polyoxypropylene polymer

0.900 mg of microcrystalline cellulose

Preparation:

Dissolve the effective substances and auxiliary substances in water at 90°C, that is, suspend the microcrystalline cellulose and evaporate the dispersion in a vacuum. Sow the dry mass to a loop width of 1 mm.

The following ingredients are mixed with the granule of the active substance for the tablet:

23,080 mg sodium carboxymethyl starch

23,000 mg of microcrystalline cellulose

0.500 mg magnesium stearate

50,000 mg

Round plan-parallel tablets of 50 mg with a diameter of 5 mm are formed from this mixture.

EXAMPLE 17

Tablet with 2.0 mg AG-EE 623 ZW

One tablet contains:

2.00 mg of active substance

1.00 mg of L-Lysine

1.00 mg polyvinylpyrrolidone

1.00 mg of polyoxyethylene polyoxypropylene polymer

4.00 mg of microcrystalline cellulose

Preparation:

Effective substances and auxiliary substances are dissolved in water at 90°C, that is, microcrystalline cellulose is suspended and the dispersion is processed in a diffusion dryer. Then we add the following ingredients for the tablet:

20.35 mg of microcrystalline cellulose

20.00 mg sodium carboxymethyl starch

0.65 mg magnesium stearate

50,000 mg

From this mixture, round biconvex tablets of 50 mg and 5 mm in diameter are formed and layered with hydroxypropyl ethyl cellulose to cover the taste.

EXAMPLE 18

Tablet with 2.5 mg AG-EE 623 ZW

One tablet contains:

2.50 mg of active substance

1.25 mg of L-lysine

1.25 mg of polyvinylpyrrolidone

1.25 mg of polyoxyethylene polyoxypropylene polymer

4.10 mg of microcrystalline cellulose

Preparation:

Effective substances and auxiliary substances are dissolved in water at 90°C, that is, microcrystalline cellulose is suspended and the dispersion is processed in a diffusion dryer. For the tablet, we then add the following ingredients:

19.50 mg of microcrystalline cellulose

19.50 mg sodium carboxymethyl starch

0.65 mg magnesium stearate

50,000 mg

Round biconvex tablets of 50 mg and 5 mm in diameter are formed from this mixture and coated with hydroxypropylmethylcellulose to mask the taste.

EXAMPLE 19

Tablet with 3.0 mg AG-EE 623 ZW

One tablet contains:

3.0 mg of active substance

1.5 mg of L-lysine

1.5 mg polyvinylpyrrolidone

1.5 mg of polyoxyethylene polyoxypropylene polymer

Preparation:

Dissolve the ingredients in water at 90°C and process the solution in a diffusion dryer. For the tablet, we then add the following ingredients:

21.5 mg of microcrystalline cellulose

21.0 mg sodium carboxymethyl starch

50.00 mg

From this mixture, round biconvex tablets of 50 mg and 5 mm in diameter are formed, and we layer them with hydroxypropyl-methylcellulose to cover the taste.

EXAMPLE 20

Tablet with 5 mg AG-EE 623 ZW

One tablet contains:

5.0 mg of active substance

2.5 mg of L-lysine

2.5 mg polyvinylpyrrolidone

2.5 mg of polyoxyethylene polyoxypropylene polymer

Preparation:

Dissolve the ingredients in water at 90°C, and process the solution in a diffusion dryer. For the tablet, we then add the following ingredients:

19.0 mg of microcrystalline cellulose

18.5 mg sodium carboxymethyl starch

50.0 mg

From this mixture, round biconvex tablets of 50 mg and 5 mm in diameter are formed, and we layer them with hydroxypropyl-methylcellulose to cover the taste.

Claims (11)

1. A compound characterized by the fact that it is (S)-(+)-2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoic acid and its salts with inorganic or organic acids or bases. 2. Compound according to claim 1, characterized in that it is essentially optically pure. 3. Compound according to claim 2, characterized in that the optical purity is at least ee = 95%. 4. Compound according to claim 2, characterized in that the optical purity is at least ee = 98%. 5. Physiologically acceptable salts, characterized by the fact that they are salts of compounds according to claims 1 to 4 with inorganic or organic acids or bases. 6. Medicine, characterized by the fact that, in addition to one or more inert carriers and/or diluents, it also contains a compound according to claims 1 to 4 or a physiologically acceptable salt according to claim 5. 7. Use of the compound according to claims 1 to 4 or its physiologically acceptable salts according to claim 5, characterized in that it is used for the treatment of diabetes mellitus. 8. Method for the preparation of medicines according to claim 6, characterized in that the compound according to claims 1 to 4 or the physiologically acceptable salt according to claim 5 is non-chemically incorporated into one or more inert carriers and/or diluents. 9. Process for the preparation of a new compound according to claims 1 to 5, characterized in that a) (S)-amine of the formula [image] chemically convert with a carboxylic acid of the general formula [image] in which it represents W carboxy group or a carboxy group protected with a protective residue, or with its, in the given example, a reactive derivative prepared in the reaction mixture and then, if necessary, cleave off the protective residue used or b) we split the (S)-compound of the general formula [image] in which it represents And with hydrolysis, thermolysis or hydrogenolysis to a carboxy group a translatable group, or c) (S)-compound of the general formula [image] in which means W' is a carboxy group or an alkoxycarbonyl group together with 2 to 5 carbon atoms, whereby the alkyl part of the alkoxy group can be substituted by a phenyl group, we convert it with a compound of the general formula [image] in which it represents With a nucleophilic exchangeable group or also together with a neighboring hydrogen atom a diazo group, and then, if necessary, the thus obtained compound is hydrolyzed or hydrogenolized or d) a compound of the general formula [image] in which it represents W' is a carboxy group or an alkoxycarbonyl group together with 2 to 5 carbon atoms, whereby the alkyl part of the alkoxy group may be substituted by a phenyl group, and Y group of the formula [image] enantioselectively reduce and then, if necessary, hydrolyze the thus obtained compound or e) we oxidize the (S)-compound of the general formula [image] in which it represents W" for oxidation to a carboxy group, a translatable group, or f) separate the mixture, which consists of any amount of (S)-enantiomer of the general formula [image] and any amount of the (R)-enantiomer of the general formula [image] in which it means W' is a carboxy group or an alkoxycarbonyl group together with 2 to 5 carbon atoms, whereby the alkyl part of the alkoxy group can be substituted by a phenyl group, and the compound thus obtained is, if necessary, transformed into a compound with higher enantiomeric purity by crystallization, whereby crystallization from ethanol/water (2 /1) we obtain a form with a high melting point of 130 to 131°C and by crystallization from petroleum ether/toluene (5/3) a form with a low melting point of 99 to 101°C, and we translate the thus obtained compound into its salts, especially into its physiologically acceptable salts with inorganic or organic acids or bases. 10. A compound characterized in that it is (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine and its acid addition salts. 11. New compounds with general formulas, indicated by that [image] [image] in which they represent And by hydrolysis, thermolysis or hydrogenolysis to the carboxy group a translatable group, W' is a carboxy group or an alkoxycarbonyl group together with 2 to 5 carbon atoms, whereby the alkyl part of the alkoxy group can be substituted with a phenyl group and W" by oxidation to a carboxy group, a translatable group, and their addition salts.